Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D251/00—Heterocyclic compounds containing 1,3,5-triazine rings
  • C07D251/02—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings
  • C07D251/12—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
  • C07D251/26—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hetero atoms directly attached to ring carbon atoms
  • C07D251/40—Nitrogen atoms
  • C07D251/54—Three nitrogen atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
  • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
  • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
  • C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems

Definitions

• the present invention relates to the preparation of a 6-fluoro-2-haloquinoline of general formula: ##STR1## in which R is a hydrogen atom or an alkyl radical, and Hal and Hal' are identical or different halogen atoms.
• the process according to the present invention is also useful for the preparation of antimicrobial 1,8-benzonaphthyridine derivatives, and it furthermore makes it possible to work under mild conditions and to obtain improved yields and avoids proceeding via unstable intermediate products.
• R represents an alkyl radical
• the latter is straight or branched and contains 1 to 4 carbon atoms
• the symbol Hal is advantageously chosen from chlorine or fluorine and the symbol Hal' is chosen from chlorine or bromine.
• the quinoline derivative of general formula (I) may be prepared by the action of a halogenating agent on the 1-hydroxyquinolone of general formula: ##STR3## in which Hal is defined as above and R 1 is defined as R with the exception of representing a hydrogen atom, optionally followed by freeing the acidic function if it is desired to obtain a quinoline derivative of general formula (I) for which R is a hydrogen atom.
• the reaction is carried out in an organic solvent such as, for example, a halogenated solvent (particularly a chlorinated solvent such as dichloromethane, 1,2-dichloroethane, 1,1,1-trichloroethane, chlorobenzene or dichlorobenzene especially) or in an aromatic solvent (for example toluene, nitrobenzene, diphenyl ether, etc.) at a temperature between 20° C. and the reflux temperature of the reaction mixture.
• a halogenated solvent particularly a chlorinated solvent such as dichloromethane, 1,2-dichloroethane, 1,1,1-trichloroethane, chlorobenzene or dichlorobenzene especially
• an aromatic solvent for example toluene, nitrobenzene, diphenyl ether, etc.
• the halogenating agent may be chosen from phosphorus trichloride, phosphorus pentachloride, thionyl chloride, sulphuryl chloride, sulphur dichloride, stannous chloride, cuprous chloride, titanium trichloride, ferrous chloride, chromium(II) chloride, triphenylphosphine hydrochloride, dichlorotriphenylphosphorane or chlorine.
• the halogenating agent may be chosen from phosphorus tribromide, triphenylphosphine hydrobromide or dibromotriphenylphosphorane.
• hydrolysis of the ester may be carried out by any known method for obtaining an acid from an ester without affecting the remainder of the molecule.
• the hydrolysis is in particular carried out in acidic medium, for example in the presence of hydrochloric acid, sulphuric acid or methanesulphonic acid. It may also be carried out in basic aqueous-alcoholic medium (for example sodium hydroxide or potassium hydroxide).
• the 1-hydroxyquinolone of general formula (II) may be obtained by cyclization of a nitro derivative of general formula: ##STR4## in which Hal and R 1 are defined as above, and R 2 is defined as R 1 or represents a carbamoyl or cyano radical, by catalytic hydrogenation in acidic medium.
• the catalytic hydrogenation is carried out in the presence of palladium on charcoal or platinum, at a temperature between 0° and 130° C., in the presence of an organic or inorganic acid which does not alter the remainder of the molecule.
• the process is performed in acetic acid or in formic acid, and it is also possible to perform the process using dilute hydrochloric acid or dilute sulphuric acid in an aqueous-alcoholic medium.
• the reaction is carried out until the hydrogen consumption decreases sharply.
• the process is preferably carried out at atmospheric pressure.
• nitro derivative of general formula (III) may be prepared by the action of a malonic acid derivative of general formula:
• the reaction is generally carried out in basic medium [for example in the presence of an alkali metal bicarbonate (sodium bicarbonate), a hydride (sodium hydride) or an alkoxide at a temperature between 0° and 150° C., in an organic solvent such as an anhydride (acetic anhydride for example) or such as an amide (dimethylformamide or N-methylpyrrolidone for example) by performing the process in the presence of molecular sieves or any other drying agent] or alternatively in a mixture of solvents such as a polar aprotic solvent/acetic anhydride mixture (dimethylformamide/acetic anhydride or N-methylpyrrolidone/acetic anhydride for example). It is also possible to perform the process in a two-phase medium. It is not essential to isolate the product of general formula (III) in order to use it in the following reaction.
• the fluoronitrobenzaldehyde of general formula (V) is obtained by nitration of the fluorobenzaldehyde of general formula: ##STR6## in which Hal is defined as above.
• the reaction is advantageously carried out using concentrated nitric acid in the form of a sulphonitric mixture, or in the form of a nitric acid/acetic acid mixture, at a temperature between 0° and 90° C.
• 4-Chloro-3-fluorobenzaldehyde may be prepared according to the method described in European Application EP 289,942.
• the preparation of the 6-fluoro-2-haloquinoline of general formula (I) is useful for the synthesis of derivatives of 1,8-benzo [b]naphthyridine of general formula: ##STR7## in which either R 3 (which represents an alkyl, fluoroalkyl, cycloalkyl containing 3 to 6 carbon atoms, alkyloxy or alkylamino radical) and Het (which is a nitrogen-containing heterocyclic radical) are as defined for the substituents in the 1- and 8-positions, in the European Application EP 431,991 and the U.S. Pat. No.
• R 3 is a hydrogen atom or an alkyl, fluoroalkyl, carboxyalkyl, cycloalkyl containing 3 to 6 carbon atoms, fluorophenyl, difluorophenyl, alkyloxy or alkylamino radical, and Het is a 1-azetidinyl radical which is substituted [in the 3-position with a radical R 4 which may be a hydrogen atom or a hydroxyl, amino or alkylamino radical in which the alkyl part is optionally substituted with an amino or hydroxyl radical or may represent a dialkylamino radical for which the alkyl parts may optionally form, with the nitrogen atom to which they are attached, a 5- or 6-membered heterocycle optionally containing another hetero atom chosen from nitrogen, oxygen or sulphur, or may represent a cycloalkylamino radical containing 3 to 6 members, or an alkanoylamino, N-alkyl-N-alkanoy
• benzonaphthyridine derivatives are particularly advantageous antimicrobial agents.
• the 1,8-benzo[b]naphthyridines of general formula (VII) may be obtained by the process according to the invention, by working in the following way:
• the benzonaphthyridine derivative of general formula (VII) may be obtained from 2-chloro- (or 2-bromo-) 6-fluoroquinolinecarboxylic acid of general formula (I) in which R is a hydrogen atom, according to or by analogy with the method described in the Application EP 431,991 or WO 93/07144, or in the U.S. Pat. No. 5,004,745 or U.S. Pat. No. 4,970,213.
• the benzonaphthyridine derivative of general formula (VII) may also be obtained from the ester of general formula (I) for which R is an alkyl radical, by working as follows:
• R 3 is defined as above and R 7 is an alkyloxycarbonyl, cyano, carbamoyl, alkylcarbamoyl, benzylcarbamoyl, hydroxyethylcarbamoyl, dialkylaminoethylcarbamoyl or dialkylcarbamoyl radical in which the alkyl parts may optionally form, with the nitrogen atom to which they are attached, a 5- or 6-membered heterocycle optionally containing another hetero atom chosen from oxygen, sulphur or nitrogen and optionally substituted on the nitrogen with an alkyl radical (the alkyl radicals being straight or branched and containing 1 to 4 carbon atoms), is condensed with the halofluoroquinoline of general formula (I) in which R is an alkyl radical, so as to obtain a fluoro ester of general formula: ##STR8## in which Hal, R 3 and R 7 are defined as above and R represents an alkyl radical.
• the condensation is carried out in basic medium in an organic solvent such as an aromatic hydrocarbon (toluene for example), an amide (dimethylformamide or N-methylpyrrolidone for example), an ether (tetrahydrofuran for example), a sulphoxide (dimethyl sulphoxide for example), a chlorinated solvent (dichloromethane, dichloroethane or chlorobenzene for example) or an alcohol at a temperature between -10° and 120° C.
• an organic solvent such as an aromatic hydrocarbon (toluene for example), an amide (dimethylformamide or N-methylpyrrolidone for example), an ether (tetrahydrofuran for example), a sulphoxide (dimethyl sulphoxide for example), a chlorinated solvent (dichloromethane, dichloroethane or chlorobenzene for example) or an alcohol at a temperature between -10° and 120° C.
• an organic solvent such as an aromatic
• the bases used may be chosen from alkali metal carbonates (sodium or potassium carbonate), alkoxides or an alkali metal hydride (sodium hydride).
• R 3 represents a carboxyalkyl radical
• the latter is protected prior to the reaction. Removal of the protecting radical is preferably carried out after the oxidation reaction, on the benzonaphthyridine derivative of general formula (XI) described below.
• the protection and the freeing of the acid function are carried out according to the usual methods which do not alter the remainder of the molecule. In particular according to the methods which have been mentioned above.
• the fluoroquinoline of general formula (IX) is cyclized in basic medium in order to prepare the 1,2,3,4-tetrahydro-1,8-benzo[b]naphthyridine of general formula: ##STR9## in which Hal, R 3 and R 7 are defined as above.
• the reaction is carried out at a temperature between -70° and 120° C. in the presence of a base such as an alkoxide (sodium ethoxide, sodium methoxide or potassium t-butoxide for example), an alkali metal hydride (sodium hydride for example), or alternatively an alkali metal hydroxide by performing the process by phase transfer.
• a base such as an alkoxide (sodium ethoxide, sodium methoxide or potassium t-butoxide for example), an alkali metal hydride (sodium hydride for example), or alternatively an alkali metal hydroxide by performing the process by phase transfer.
• a base such as an alkoxide (sodium ethoxide, sodium methoxide or potassium t-butoxide for example), an alkali metal hydride (sodium hydride for example), or alternatively an alkali metal hydroxide by performing the process by phase transfer.
• the process is advantageously carried
• the oxidation is carried out using hydrogen peroxide, optionally in the presence of potassium iodide, in an organic solvent such as an alcohol (ethanol for example), at a temperature between 0° and 120° C. It is also possible to perform the process in a two-phase medium in a water/chlorinated solvent (dichloromethane, dichloroethane, etc.) mixture.
• the heterocycle Het is condensed with the 1,8-benzo[b]naphthyridine of general formula (XI) or the corresponding acid in order to prepare a benzonaphthyridine derivative of general formula (VII), by performing the process according to or by analogy with the methods described in European Application EP 431,991 and the U.S. Pat. No. 5,004,745 followed, where appropriate, by conversion of the ester, the amide or the nitrile obtained to an acid of general formula (VII).
• the benzonaphthyridine derivatives of general formula (VII) are antimicrobial agents whose activities have been described in the European Application and the American Patent mentioned above.
• the products arising from the process according to the present invention, as well as the products to which they lead, may optionally be purified by physical methods such as crystallization or chromatography.
• 3-Ethoxycarbonyl-6,7-difluoro-1-hydroxy-2-oxoquinoline may be prepared in the following way:
• Ethyl (3,4-difluoro-6-nitrobenzylidene)malonate may be prepared in the following way:
• reaction mixture After cooling to 0° C., the reaction mixture is poured onto slushed ice (250 g of ice +250 g of water at 0° C.) and left to separate overnight. The organic phase is washed with saturated NaHCO 3 solution (100 cm 3 ), followed by water (100 cm 3 ), and then concentrated to dryness in order to obtain 19.8 g of 3-ethoxycarbonyl-6,7-difluoro-2-chloroquinoline of 90% assay (HPLC), equivalent to a yield of 88%.
• HPLC 3-ethoxycarbonyl-6,7-difluoro-2-chloroquinoline of 90% assay
• the products obtained by the process according to the invention may be used in the following way:
• 2-Chloro-3-ethoxycarbonyl-6,7-difluoroquinoline is converted to 2-chloro-6,7-difluoro-3-quinolinecarboxylic acid according to the usual methods and may thus lead to the 1,8-benzo[b]-naphthyridine derivatives described in the U.S. Pat. No. 4,970,213.
• a solution of 11.4 g of sodium thiosulphate in 50 cm 3 of water are poured in over 5 minutes at this temperature.
• the precipitate obtained is filtered off at approximately 20° C. and washed with twice 300 cm 3 of water.
• the moist product obtained is dried under reduced pressure (20 kPa) at approximately 60° C.
• 73 g of 3-ethoxycarbonyl-7,8-difluoro-1-methyl-4-oxo-1,4-dihydro-1,8-benzo[b]naphthyridine are isolated, in the form of a white solid melting at a temperature greater than 270° C.
• the precipitate obtained is filtered off at approximately 20° C. and is washed with twice 20 cm 3 of water.
• the moist product obtained is dried under reduced pressure (20 kPa) at approximately 50° C. 8 g of 3-cyano-7,8-difluoro-1-methyl-4-oxo-1,4-dihydro-1,8-benzo[b]naphthyridine are isolated, in the form of a light yellow solid melting at 380° C.
• a suspension of 2.1 g of 3-cyano-7,8-difluoro-1-methyl-4-oxo-1,4-dihydro-1,8-benzo[b]naphthyridine in 100 cm 3 of dimethyl sulphoxide is heated at 80° C. in the presence of 2 cm 3 of N-methylpiperazine.
• the reaction mixture is maintained at this temperature for 8 hours.
• the solution obtained is cooled to room temperature and stirred at this temperature for 15 hours.
• the precipitate formed is filtered off, washed with 3 times 20 cm 3 of water and dried under vacuum (20 kPa) at 50° C.
• a suspension of 2 g of 3-cyano-7-fluoro-1-methyl-8-(4-methyl-1-piperazinyl)-4-oxo-1,4-dihydro-1,8-benzo[b]naphthyridine is heated at reflux in 40 cm 3 of 12N hydrochloric acid.
• the reaction mixture is maintained at this temperature for 15 hours.
• the solution obtained is cooled to room temperature.
• the product which crystallizes is filtered off, washed with water until neutral, and dried under reduced pressure (20 kPa) at 50° C.
• 35 g of 3-ethoxycarbonyl-6,7-difluoro-2-[N-methyl-N- ⁇ -(N',N'-dimethylaminocarbonylethyl)amino]quinoline are obtained in the form of an oil, which is used without further purification for the subsequent steps.
• N,N-Dimethyl-7,8-difluoro-1-methyl-4-oxo-1,2,3,4-tetrahydro-1,8-benzo[b]naphthyridine-3carboxamide is prepared in the following way:
• the crude reaction mixture is taken up in 200 cm 3 of an aqueous-alcoholic ethanol/water mixture (70/30 vol/vol).
• the precipitate obtained is filtered off, washed 3 times with 100 cm 3 of water and then dried under vacuum (20 kPa).
• 25 g of N,N-dimethyl-7,8-difluoro-1-methyl-4-oxo-1,2,3,4-tetrahydro-1,8-benzo[b]naphthyridine-3-carboxamide are isolated, in the form of a lemon yellow solid melting at 206° C.
• N,N-Dimethyl-7,8-difluoro-1-methyl-4-oxo-1,4-dihydro-1,8-benzo[b]naphthyridine-3-carboxamide is prepared in the following way:
• a suspension of 2.96 g of 7,8-difluoro-N,N-dimethyl-4-oxo-1-methyl-1,4-dihydro-1,8-benzo[b]-naphthyridine-3-carboxamide, 1.12 g of 1-methylpiperazine and 1.55 g of potassium carbonate in 100 cm 3 of dimethyl sulphoxide is heated for 5 hours at approximately 80° C., with stirring. After cooling to approximately 20° C., 100 cm 3 of water are added to the reaction mixture; the insoluble product is filtered off, and washed with twice 30 cm 3 of water and twice 30 cm 3 of ethanol.
• the product obtained is suspended in 30 cm 3 of water; 0.6 cm 3 of 1N aqueous potassium hydroxide is added and stirring is carried out for 1 hour at approximately 20° C.
• the insoluble product is filtered off, and washed with twice 20 cm 3 of water and twice 10 cm 3 of ethanol.
• After recrystallization in 15 cm 3 of dimethylformamide 0.15 g of 7-fluoro-1-methyl-8-(4-methyl-1-piperazinyl)-4-oxo-1,4-dihydro-1,8-benzo[b]naphthyridine-3-carboxylic acid is obtained, in the form of a yellow solid decomposing at 354° C.
• the crude reaction mixture is taken up in 10 cm 3 of an aqueous-alcoholic ethanol/water mixture (70/30 vol/vol).
• the precipitate obtained is filtered off, washed with 3 times 10 cm 3 of water, and then dried under reduced pressure (20 kPa).
• 1.6 g of 7,8-difluoro-1-methyl-4-oxo-1,2,3,4-tetrahydro-1,8-benzo[b]napthyridine-3-carboxamide are isolated, in the form of a yellow solid melting at 182° C.
• the precipitate obtained is filtered off at approximately 20° C. and is washed with twice 5 cm 3 of water.
• the moist product obtained is dried under reduced pressure (20 kPa) at approximately 50° C.
• 1.1 g of 3-carboxamido-7,8-difluoro-1-methyl-4-oxo-1,4-dihydro-1,8-benzo[b]naphthyridine are isolated, in the form of an orange-coloured solid melting at 318° C.
• a suspension of 1.3 g of 7,8-difluoro-1-methyl-4-oxo-1,4-dihydro-18-benzo[b]naphthyridine-3-carboxamide, 0.54 g of 1-methylpiperazine and 0.75 g of potassium carbonate in 25 cm 3 of dimethyl sulphoxide is heated at approximately 80° C. for 6 hours. After cooling to a temperature in the region of 20° C., 100 cm 3 of water are added to the reaction mixture. The insoluble product is filtered off, and washed with twice 20 cm 3 of water and twice 20 cm 3 of ethanol.
• the product obtained is chromatographed on 20 g of silica gel (0.063-0.200 mm) suspended in a mixture of dichloromethane containing 10% of methanol.
• the reaction impurities are removed by eluting with 500 cm 3 of this mixture of solvents.
• the expected product is subsequently eluted with 500 cm 3 of the same mixture of solvents.
• the solid residue is crystallized in 25 cm 3 of dimethylformamide, filtered off and washed with twice 30 cm 3 of ethanol at approximately 70° C.
• 7-Fluoro-8-(4-methyl-1-piperazinyl)-1-methyl-4-oxo-1,4-dihydro-1,8-benzo[b]naphthyridine-3-carboxylic acid is prepared under the conditions of Example of use 2, but starting from 0.3 g of 7-fluoro-1-methyl-8-(4-methyl-1-piperazinyl)-4-oxo-1,4-dihydro-1,8-benzo[b]naphthyridine-3-carboxamide. After cooling to approximately 20° C., 50 cm 3 of water are added to the reaction mixture; the insoluble product is filtered off and washed with twice 10 cm 3 of water.
• the product obtained is suspended in 20 cm 3 of water, 0.4 cm 3 of 1N aqueous potassium hydroxide solution is added thereto and stirring is carried out for 1 hour at approximately 20° C.
• the insoluble product is filtered off, washed with 3 times 10 cm 3 of water and twice 10 cm 3 of ethanol and recrystallized in 20 cm 3 of dimethylformamide.

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Nitrogen Condensed Heterocyclic Rings (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Plural Heterocyclic Compounds (AREA)
• Quinoline Compounds (AREA)
• Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
• Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

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Citations (12)

• 1993
  • 1993-04-08 FR FR9304163A patent/FR2703681B1/fr not_active Expired - Fee Related
• 1994
  • 1994-04-07 DE DE69409101T patent/DE69409101T2/de not_active Expired - Fee Related
  • 1994-04-07 AU AU65408/94A patent/AU680493B2/en not_active Ceased
  • 1994-04-07 NZ NZ265072A patent/NZ265072A/xx unknown
  • 1994-04-07 TW TW083103037A patent/TW261612B/zh active
  • 1994-04-07 SK SK1256-95A patent/SK281139B6/sk unknown
  • 1994-04-07 CZ CZ952600A patent/CZ283705B6/cs not_active IP Right Cessation
  • 1994-04-07 EP EP94913146A patent/EP0693060B1/fr not_active Expired - Lifetime
  • 1994-04-07 CA CA002158746A patent/CA2158746C/fr not_active Expired - Fee Related
  • 1994-04-07 DK DK94913146T patent/DK0693060T3/da active
  • 1994-04-07 ES ES94913146T patent/ES2114189T3/es not_active Expired - Lifetime
  • 1994-04-07 WO PCT/FR1994/000391 patent/WO1994024113A1/fr active IP Right Grant
  • 1994-04-07 KR KR1019950704416A patent/KR100330141B1/ko not_active IP Right Cessation
  • 1994-04-07 IL IL10925594A patent/IL109255A/xx active IP Right Grant
  • 1994-04-07 AT AT94913146T patent/ATE164155T1/de not_active IP Right Cessation
  • 1994-04-07 HU HU9502934A patent/HU221861B1/hu not_active IP Right Cessation
  • 1994-04-07 JP JP52281694A patent/JP3666753B2/ja not_active Expired - Fee Related
  • 1994-10-20 US US08/448,404 patent/US5624933A/en not_active Expired - Fee Related
• 1995
  • 1995-10-02 NO NO953914A patent/NO305752B1/no unknown
  • 1995-10-05 FI FI954750A patent/FI113263B/fi not_active IP Right Cessation
• 1998
  • 1998-03-19 GR GR970402800T patent/GR3026401T3/el unknown

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